The increasing prevalence of drug-resistant bacteria in the clinical setting has necessitated the need for new antibacterial agents. According to the 2013 report by the Centers for Disease Control and Prevention, antibiotic resistance infections resulted in more than 2,049,442 illnesses and 23,000 deaths. Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) alone are responsible for approximately 100,000 infections and about half of the deaths each year. With these dangerous infections raging in the clinic, there is a desperate need for new antibiotics. While modification of tried and true scaffolds is the simplest method for generating new antimicrobials, new scaffolds with novel targets are needed. Most current classes of antibiotics were discovered during the “golden era” of antibiotic research from the 1930s to the 1970s. However, from the early 1970s to 1999, only one new class of antibiotic was launched. Although the situation has improved somewhat with the approval of five new classes of antibiotics since 2000, the statistics presented above show that there is still a desperate need for new classes of antibiotics with novel modes of actions that will not exhibit cross-resistance with those currently on the market.
Orthosomycins, polysaccharides defined by an orthoester linkage, are an underexplored class of antibiotics. Everninomicins are broad spectrum orthosomycin antibiotics produced by the soil bacterium Micromonospora carbonacea and that display activity against a variety of Gram-positive organisms including MRSA and VRE. To date, fourteen everninomicins have been reported. FIG. 1 shows the variety of everninomicins isolated from Micromonospora carbonacea. All everninomicins, with the exception of Ever-2, which lacks the A ring nitrosugar, are octasaccharides containing dichloroisoeverninic acid. The majority of everninomicins also contain orsellinic acid at the opposite end of the saccharide chain. Everninomicins possess three unique oxidative features. The first is a methylenedioxy bridge attached to ring F. The second is its namesake orthoester linkages located between rings C and D and rings G and H. Finally, L-evernitrose (ring A) is a nitrosugar unique to everninomicins. In contrast with the other polysaccharides, the everninomicins contain a large proportion of deoxy sugars. Rings A, B (D-olivose), and C (D-olivose), and sometimes ring D (D-evalose) are all 2,6-dideoxy sugars while ring E (4-O-methyl-D-fucose) is 6-deoxygenated. Ring F is 2,6-di-O-methyl-D-mannose, ring G is L-lyxose, and ring H is eurekanate.
Avilamycins, produced by Streptomyces viridochromogenes Tü57, are heptasaccharides similar to everninomicin but lacking the nitrosugar. At least sixteen avilamycins have been characterized to date (FIG. 1). Avilamycins have the same seven-sugar core as the everninomicins. All avilamycins contain dichloroisoeveminic acid but lack orsellinic acid at the eastern side of the molecule. The main points of differentiation among the avilamycins are the decorations of rings G and H. As in the everninomicins, the avilamycins also contain a methylenedioxy bridge and two orthoester linkages located between rings C and D and rings G and H.
Interest in the everninomicins peaked in the early 2000s when Schering-Plough Corporation (now Merck & Co.) was developing everninomicin A (Ziracin) as an antimicrobial agent. Everninomicin A (1) advanced to phase III clinical trials before being discontinued due to a poor balance between efficacy and safety. However, investigation of the orthosomycins is still of interest as members of this class possess potent activity against clinically important strains such as methicillin-resistant staphylococci, glycopeptide-resistant enterococci, vancomycin-resistant enterococci, and penicillin-resistant streptococci, and may be effective for treating infective endocarditis.
The orthosomycins act as bacterial translation inhibitors; although, they target a different site on the large ribosomal subunit than other antibiotics currently on the market. Everninomicin has been shown to bind to a unique site on the 50S ribosomal subunit and prevent formation of the 70S initiation complex in an IF2 dependent manner thereby inhibiting bacterial translation. Specifically, everninomicin appears to interact with ribosomal protein L16 and r23S RNA helices 89 and 91 (FIG. 2). Everninomicin is also a potent inhibitor of back-translocation by inhibiting the GTPase activity of EF-4.
Due to their activity against a variety of drug-resistant Gram-positive bacteria as well as their novel bacterial targets, the orthosomycins can be clinically useful drugs. Nature has already provided a variety of everninomicins to begin understanding their structure-activity relationship. This is encouraging as the natural pathway appears to contain some flexibility and promiscuity as to substrates. Unfortunately, making analogs by chemical synthesis is impractical as the total synthesis involves over 130 steps. Therefore, there is a need to access new eveminomicin congeners with pharmacological and biological properties. The methods and compositions disclosed herein address these and other needs.